Human immunodeficiency virus type I and type II (HIV-1 and HIV-2, hereinafter referred to collectively as "HIV") are recently discovered retroviruses. HIV exerts a profound cytopathic effect on the CD4+ helper/inducer T-cells, devastating the function of the immune system, and also causes neurological deterioration. The virus is the etiologic agent of the acquired immune deficiency syndrome (AIDS) and related diseases such as AIDS Related Complex (ARC).
AIDS is an ailment of worldwide concern. The World Health Organization estimates that by 1992, the number of AIDS cases will be about 1.2 million.
The field of viral chemotherapeutics has developed in response to the need for agents effective against retroviruses, particularly HIV. There are many ways in which an agent can exhibit antiretroviral activity, one of which is through inhibition of viral replication. For example, the HIV virus requires at least four viral proteins for replication: Reverse Transcriptase (RT), protease, the transactivator protein TAT, and the REV protein. Anti-retroviral agents such as AZT or ddC are known to be RT inhibitors. Other agents such as TAT inhibitors act at a different stage of the viral life cycle.
HIV replication in latently infected CD4+ lymphocytes is induced when the cells are stimulated to proliferate by cytokines or mitogens. The switch from viral latency to active replication requires the regulatory gene products TAT and REV. The TAT protein transactivates the HIV-LTR promoter and amplifies viral replication many thousand fold. The TAT responsive sequence is mapped within the LTR sequence. Compounds which have anti-HIV-TAT activity will arrest HIV at the latent stage of viral infection by preventing transcription of the provirus that is integrated into the host cell chromosome. Anti-TAT agents are thus useful for therapeutically treating patients infected with HIV, including AIDS and ARC patients, and other symptomatic and asymptomatic carriers of the virus.
A summary of antiviral drugs being investigated for the treatment of AIDS, including AZT, is provided in U.S. Pat. No. 4,788,181. It is noteworthy, however, that the data on patients treated with AZT, the only compound now approved for AIDS therapy, indicates that AZT does not eliminate viremia in patients, and eventually the appearance of drug-resistant mutant viruses is evidenced. Consequently, there is still a great need for therapeutic agents for the treatment and alleviation of AIDS and AIDS related diseases and symptoms.
Certain 3H-1,4-benzodiazepine compounds containing a 5-membered heterocyclic ring as a substituent in the 5-position are taught in U.S. Pat. Nos. 3,405,122, 3,400,128, 3,398,159 and 3,407,211. In particular, formula IV, column 1, of each of these patents discloses the generic structure for several substituted amino-3H-1,4-benzodiazepine compounds. However, the specification provides no specific example of such substituted amino compound. Moreover, these compounds are disclosed to be useful as sedatives, convulsants, tranquilizers or muscle relaxants.
Unexpectedly, applicants have discovered that certain novel substituted 2-amino-3H-1,4-benzodiazepine compounds exhibit antiviral properties; in particular, they have anti-HIV and anti-HIV-TAT activity. These compounds are useful as antiviral agents, in particular in the treatment, therapy or prophylaxis of AIDS and AIDS-related diseases.